Project Summary The orexin receptor is a G-protein-coupled receptor that binds the neuropeptide hormone orexin, also known as hypocretin. There are two variants of the receptor, OX1 and OX2, each encoded by a different gene. Orexin receptors are associated with many neurological diseases, including drug addiction. There are growing evidences to support a role for orexin in responses to substances of abuse, including methamphetamine, amphetamine, nicotine, cocaine, morphine and alcohol. Small molecule orexin therapeutics has already demonstrated promise in animal models of drug abuse; antagonism of the OX1 receptor has been shown to reduce self-administration or relapse illicit drugs and alcohol. Unfortunately, there are no suitable non-invasive imaging tools for investigating these processes in animals or in human. The development of techniques for visualizing orexin receptors in vivo represents a key step in understanding both the normal function and pathophysiology of the orexin system in brain. The project is designed to develop a novel PET imaging probe for OX1 receptor. We will label OX1 selective antagonists with carbon-11 or fluorine-18 and evaluate the potential of these molecules to serve as radiotracers for orexin 1 receptors in rodents and non-human primates. We will develop the first PET imaging agent to investigate role of orexins in drug addiction.